4-nitropyrazole-5-carboxamidoximes

ABSTRACT

SUBSTITUTED 4-NITROPYRAZOLE-5-CARBOXAMIDOXIMES AND SUBSITUTED 3-(4-NITROPYRAZOL-5-YL)-4,5-DIHYDRO-1,2,4-OXADIAZOLES, PREPARED, INTER ALIA, FROM THE CORRESPONDINGLY SUBSTITUTED 4-NITRO-5-CYANO-PYRAZOLES, ARE DESCRIBED. THE END PRODUCTS OF THE INVENTION POSSESS PYSCHOSEDATIVE ACTIVITY AND ARE THEREFORE USEFUL AS TRANQUILIZING AGENTS.

'fore useful as tranquilizing agents.

3,822,283 4-NITROPYRAZOLE-5-CARBOXAMIDOXIMES Hans Bruderer, Benken, Rolf Richie, Mohlin, and Rudolf Ruegg, Bottmingen, Switzerland, assignors to Hotfmann-La Roche Inc., Nutley, NJ.

Filed Oct. 11, 1972, Ser. No. 296,691

Int. Cl. C 1d 49/18 U.S. 01.260-310 R 16 Claims ABSTRACT OF DISCLOSURE I Substituted 4-nitropyrazole-5-carboxamidoximes and substituted 3-(4-nitropyrazol-5-yl)-4,5dihydro-1,2,4-oxadiazoles, prepared, inter alia, from the correspondingly substituted 4-nitro-5-cyano-pyrazoles, are described. The end products of the invention possess psychosedative activity I and are therefore useful as tranquilizing agents;

United States Patent lower alkyl orlower all oxy and R isa group of the wherein R is hydroxy,lower alkanoyloxy, lower alkoxycarbonyloxy, lower alkoxy, lower alkoxy substituted with 'halogen or lower alkoxy, phenylcarbonyloxy, phenyl- (lower alkylcarbonyloxy), phenyl-(lo'wer alkenylcarbonyl- 'oxy), pyridyl-(lower alkylcarbonyloxy) or pyridylcarbonyloxy (the phenyl residues and the pyridyl residues being optionally substituted with lower alkyl, loweralkoxy or halogen); R is lower alkyl or phenyl and R is hy- 'drogen or lower alkyl or R and R together with the carbon atom towhich they are attached comprise a ,5-, 6- or 7-memberedfalicyclic ring, or 'pharrnace'utically acceptable acid' addition salts thereof. The compounds of formula I possess psychosedative activity Detailed Description of the Invention The pyrazolederivatives provided by the characterized by the formula V a v ;NOI.

invention are EFF- lower alkyl,-carboxy-lower alkyl or lower alkenyl; R is and are therehydrogen, halogen, lower alkylorlower alkoxy and-R wherein R is lower alkyl, halo-lower-alkyl, hydroxy-loweralkyl', ;lower, alkoxy-lower alkyl, lower alkoxy-carbonyl- *alkoxyphenyl-( lower 3,822,283 Patented July 2, 1974 wherein R is hydroxy, lower alkanoyloxy, lower alkoxycarbonyloxy, lower alkoxy, halo-lower alkoxy,"lower alkoxy-lower al'koxy, phenylcarbonyloxy, lower alkylphenylcarbonyloxy, lower alko-xy-phenylcarbonyloxy, halo-phenylcarbonyloxy, phenyl-(lower alkylcarbonyloxy), lower alkylphenyl-(lower alkylcarbonyloxy), lower alkylcarbonyloXY), halo-phenyl- (lower alkylcarbonyloxy) phenyl-(lower alkenylcarbonyloxy), lower alkyl-phenyl-(lower alkenylcarbonyloxy), lower alkoxy-phenyl-(lower alkenylcarbonyloxy), halophenyl-(lower alkenylcarbonyloxy), pyridyl-(lower alkylcar bonyloxy), lower alkyl-pyridyl-(lower alkylcarbonyloxy), lower alkoxy-pyridyl-(lower alkylcarbonyloxy), halo-pyridyl-(lower alkylearbonyloxy), pyridylcarbonyloXy, lower alkyl-pyridylcarbonyloxy, lower alkoxy-pyridylcarbonyloxy, or halo-pyridylcarbonyloxy; R is lower alkyl or phenyl; and R is hydrogen or lower alkyl, or R and R taken together with the carbon to which they are attached, are a 5-, 6- or 7-membered alicyclic ring, or phar-maceutically acceptable acid addition salts thereof. The pyrazole derivatives of the invention, that is, the compounds of formula I and their pharmaceutically acceptable acid addition salts, can be prepared as follows:

(a) reacting a compound of the formula N H: R R (I the formula v i NOE wherein R and R are as previously described; or

(b) reacting an amidoxime of formula VI with an alkylating agent, an appropriate acylating agent or a chloroformic acid lower alkyl ester; or

(c) reacting an amidoxime of formula V1 with a carbonyl compound of the formula I R, (VII) wherein R and R are as previously described, or an acetal thereof;

(d) separating a racemate obtained into its optical antipodes, if desired; and

(e) converting a compound obtained into a salt, if desired.

As usedhereimthe term lower alkyl alone or in combinations, such as lower alkoxy, lower alkoxycarbonyl, phenyl-(lower alkylcarbonyloxy), lower alkoxycarbonyloxy or pyridyl-(lower alkylcarbonyloxy), denotes a straight chain and branched chain hydrocarbon group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and the like. The term lower alkenyl denotes a straight chain and branched chain unsaturated hydrocarbon group having 2. to 5 carbon atoms, such as allyl, propenyl, butenyl, pentenyl and 1,1-dimethylpropenly. The lower C N Hz Preferred compounds of formula I are those in is lower alkyl and R is hydrogen or lower alkyl. Other of theformula the formula alke'nyl moiety of the phenyl-(lower alkenylcarbonyloxy)"group is as described above. The term alkanoyloxy denotes a straight chain and branched chain aliphatic carboxylic acid residuehaving 1 to 5 carbon atoms, such asfacetoxy, propionyloxy, butyryloxy and the like. The term halogen denotes fluorine, chlorine, bromine and iodine; preferred is chlorine. Exemplary 055-, 6- and -7-membered alicyclic rings are cyclopentyl, cyclohexyl and cyclohep'tyl.

which R preferred compounds are those in which R is a radical rs-R,

wherein R is as previously described, and particularly preferred are those in which R is (lower alkoxy).

Another preferred group of a1koxy)-(lower compounds of. formula I comprises thosecompounds in which R is a radical-of.

wherein R and R are as previously described. Particularly preferred compounds of this group are those in which R, is lower alkyl, prefrerably methyl, or phenyl and R is hydrogen or R and R independently, are lower alkyl, preferably methyl.

Exemplary of the compounds of formula I are:

1,3-dimethyl-4-nitropyrazole-5-carboxamidoxime; 3-methyl-4-nitro-1-propylpyrazole-S-carboxamidoxime; 1-methyl-4-nitropyrazole-S-carboxamidoxime;

1-(2-hydroxyethyl)-3-methyl-4-nitropyrazole-5-1 carboxamidoxime; 1,3-O-trimethyl-4-nitropyrazole-5-carboxarnidoxime; 1-vinyl-3-methyl-4-nitropyrazole-S-carboxamidoxime; O-ethyl-l ,3-dimethyl-4-nitropyrazole-S-carboxamidoxime; O-propyy-1,3-dimethyl-4-nitropyrazole-5-carboxamidoxime; O-acetyl-1,3-dimethyl-4-nitropyrazole-S-carboxamidoxime;

O-propionyll ,3-dimethyl-4 nitropyrazole 5 carboxamidoxime; O-(3-chloropropionyl)-1,3-dimethyl-4-nitropyrazoler S-carboxamidoxime; O-butyryll,3-dimethyl-4-nitropyrazole-5-carboxamidoxime;

, O-benzoyl-1,3-dimethyl-4-nitropyrazole-5-carboxamidoxime; O-(p chlorobenzoyl)-1,3-dimethyl-4-nitropyr'aiole?. I 5-carboxamidoxi me; 4 7. O-(3,4,5-trimethoxybenzoyl)-l,3-dimethyl-4-nitropyrazole-S-carboxamidoxime;

I O-nicotinoyl-1,3-dimethyl-4-nitropyrazole-5- carboxamidoxime; O-isonicotinoyl-l,3-dimethyl-4-nitropyrazoler5:

carboxamidoxime;

O-isonicotinoyl-l-rnethyl-4-nitropyrazole-S-carboxamidoxime; I O-cinnamoyl-1,3-dimethyl-4-nitropyrazole-S-carboxamidoxime;

' O-phenylacetyl-1,3-dimethyl-4-nitropyrazole-5-carbox I amidoxime; O-hydrocinnamoyl-1,3-dimethyl-4-nitropyrazole-5- carboxamidoxime;

carried out in aii open vessel. Preferably,v the reaction O-isobutoxycarbonyl-1,3-dimethyl-4-nitropyrazole-5- carboxamidoxime; O-(2-bromoethoxy)carbonyl-1,3-dimethyl-4-nitropyrazole- S-carboxam idoxime;..- fj 11 O-allyloxycarbonyl-1,3-dimethyl-4;nitropyrazole-5- carboxamidoxime;

pyrazol-S-carboxamidoxime; I

3-( 1,3 -dimethyl:i-ititropyrazoleiS -y1 -4,5-dihydro- 5 methyl-l,2,4-oxadiazole;

3-( 1,3-dimethyl 4 nitropyrazol-5-yl -4,5-dihydro-5- propyl-1,2,4-oxadiazole;

3-( 1,3'-dimethyl 4'nit'ropyrazole-5-yl)-4,5-dihydro- 5-phenyl-1,2,4-oxadiazole;

diazaspiro [4,5] dec-Z-ene, 3-(1,3-dimethyl-4-nitropyrazol-5-yl)-4,5-dihydro-5,5-

dimethyl-1,2,4-oxadiazole; 1 4,5 -dihydro-5 -methyl-3- 3-met'hyl-4-nitro-l-propylpyrazol-5-yl)-1,2,4-oxadiazole; '3-(1-methyl-4-nitropyrazol-S-yl)-4,5-dihydro-5-methyl- 1,2,4-oxadiazole;'-

' O-methoxymethyl-1,3,-dimethyl-4-nitropyrazole-5-- ca'rboxamidoxime; andsthe like.

' In accordance with Step (a) of the process for preparing the compounds of formula I, the amidoximes of formula VI are prepared by reacting a compound of formula :II, III, IV or'Vwith hydroxylamine. This reaction is carried outinan inert solvent, for example, a lower alkanol,"'preferably methanol or ethanol, dimethylformamide, dimethylsulfoxide, a chlorinated hydrocar bon, preferably methylene. chloridev or chloroform, an ether such as dioxane 'or diethyl'ether, a hydrocarbon such as benzene,o r the like; The reaction is advantageous ly carried out at a temperature in the range of. from about 0 Cfto about the boiling'point of thereaction mixture. It is particularly pre'ferredto carry out thereac tion'at a temperature in the range of from about 40 C, to about 60 C. The pressure at which the reaction iscarried out is not critical; the reaction is preferably is carried out by the exclusion of water whena nitrile of formula II is used as the startingmaterial because in the presence ofwater' troublesome amounts-of the corresponding amide are obtained as a, result of side-reactions. The working-up of the reaction mixture is carried out in the-usual manner by removal of the solvent and recrystallization of the residue.

In accordance with an embodiment of Step (b) of the process of the invention, an amidoxime of formula VI is reacted with an alkylating agent. Depending on the choice of the alkylating agent, there are obtained compounds of formula I wherein R is lower alkoxy which may be substituted with halogen or lower alkoxy. Thus,

for example, when methyl iodide is used as the alkylating :agentthere is obtained from theamidox'ime'a compound of formula I wherein R is methoxy. Anessential feature of "this-'alkylating reaction in the prior conversion of the .;a.midoximest'arting material of'for'mula'VI into an alkali metal or alkaline earth metal salt. For this purpose, an amidoxime of formula VI is dissolved in a lower alkanol, preferably methanol or ethanol, and the mixture treated with an alkali metal or alkaline earth metal alcoholate, preferably sodium methylate or sodium ethylate. This salt formation can also be advantageously carried out in dimethylformamidewith the addition of an alkali metal or alkaline earth metal hydride.

A salt prepared thismanner is reacted with the alkylating agent in an inert organic solvent, preferably in the same solvent which was used for the salt formation. As the alkylating agents there can be used, for example, alkyl halides-fluorides-, alkylsulfonyloxy compounds, preferably mesyloxy compounds or arylsulfonyloxy compounds, preferably tosyloxy compounds. The reaction is advantageously carried out at a temperature in'the range of about C. to about the boiling point of the reaction mixture, preferably at the reflux temperature. When a special alkylating agent such as a (lower alkoxy)- (lower alkyl) halide, for example, methoxymethyl chloride, is used, it is desirable to carry out the reaction at a temperature below 0C., preferably at a temperature in the range of about 30 'C. to about -50 C. The pressure at which the reaction is carried out is not critical; thus, the reaction can be carried out in an open vessel.

In accordance with another embodiment of step (b) of the process of the invention, an amidoxime of formula VI is reacted with a suitable functional derivative of a carboxylic acid corresponding to the acyl group denoted by R;, in formula I, for example, a lower alkanecarboxylic acid such as acetic acid, or a lower arylcarboxylic acid such as benzoic acid. Examples of suitable reactive functional derivatives of carboxylic acids which can be used for the acylation of an amidoxime of formula W are anhydrides, for example, acetic anhyride, chloroacetic acid anhydride and the like, acid halides, for example, acetyl chloride, isonicotinoyl chloride hydrochloride, nicotinoyl chloride and the like, imidazolides, for examples, picolinic acid imidazolide, methoxyacetic acid imidazolide, nicotinic acid imidazolide and the like, as well as other derivatives suitable as acylating agents.

The reaction conditions are not critical and can readily be selected by any person skilled in the art depending on the carboxylic, acid derivative chosen as the acylating agent. For example, the reaction can be carried out at room temperature or at a temperature above or below room temperature, depending on the reagent chosen. In addition, it is expedient to carry out the reaction in a conventional inert organic solvent, for example, a hydrocarbon such as benzene, toluene and the like, a chlorinated hydrocarbon such as methylene chloride and the like, an ether such as tetrahydrofuran and the like, dimethylformamide, pyridine and the like. a

[In accordance with a further embodiment of Step (b) of the process of the invention, an amidoxime of formula VI is reacted with a chloroformic acid lower alkyl ester, conveniently in an inert organic solvent, for example, pyridine, an ether such as, preferably, dioxane or tetrahydrofuran, a chlorinated hydrocarbon such as chloroform or methylene chloride, or the like. Advantageously, this reaction is carried out at a temperature in the range of from about 0 C. to about 40 C., preferably from about :0 C. to about room temperature.

In accordance with Step (0) of the process of the in vention, amidoxime of formula VI is reacted with a carbonyl compound of formula VII or an acctal thereof. The

reaction parameters such as solvent, temperature,-re-

action time and pressure can be varied in a manner which is known and obvious to a person skilled in the art. Thus, the reaction can be carried out in an inert organic solvent or inv the absence of a solvent. It will be evident that when a solvent having a boiling point below the reaction temperature is used, the reaction is carried out in a closed system, for example, in an autoclave or a bomb-tube. If the boiling point of the solvent lies in the neighborhood of the reaction temperature, the reaction can be carried 'out under reflux conditions and,' if it lies above such as benzene and toluene, halogenated hydrocarbons uch as chloroform and dichloroethylene, and highly polar solvents such as dimethylformamide.

The pressure at which the reaction is carried out is not a critical feature for this reaction and as mentioned earlier, it can be carried out in an open or closed system, that is, at normal pressure or at an elevated pressure.

A favorable temperature for the reaction of an amidoxime of formula VI with a carbonyl compound of formula VII or an acetal thereof is in the range of about 50 C. to about 150 0., preferably between about C. and about C. Temperatures below 20 C., however, are not desirable for technical purposes, namely, the rate of reaction is too slow.

' Examples of acetals of the carbonyl compounds of formula VIII which can be used in embodiment (c) hereinbefore are lower alkyl acetals, preferably diethyl acetal.

With particular regard to temperature, quite generally an upper limit is set, namely, one at which decomposition of the starting material and/or the reaction product occurs. This applies to all embodiments of the process de scribed herein.

In accordance with process variant (d), the optically active antipodes of the compounds of formula I can be obtained from the corresponding racemate. The separation or resolution is carried out according to known methods,- that is, by reacting the racemate with a suitable optically active acid, separation of the two diastereoisomeric salts obtained, for example, by fractional crystallization, and subsequent liberation of the optically uniform base.

The compounds of formula I which possess more than one asymmetric center can occur in various diastereoisomeric forms. According to a further embodiment of the present process, mixtures of such diastereoisomers can be resolved according to known methods into the individual racemates which can, in turn, be separated into their optically active components in the manner described earlier.

The compouds of formula I are basic or also partially amphoteric and the preparation of their salts, especially those which are pharmaceutically acceptable, are also part of the invention. Such salts can be prepared from the corresponding bases according to generally known methods by reaction with suitable inorganic or organic acids. Exemplary of organic and inorganic acids which can be used for the preparation of pharmaceutically acceptable salts are hydrochloric acid, hydrobrornic acid, sulfuric acid, acetic acid, succinic acid, maleic acid, methanesulfonic acid, .benzenesulfonic acid, p-toluene-sulfonic acid or the like. The non-pharmaceutically acceptable acid addition salts of the compounds of formula I are suitable as intermediates for the manufacture of corresponding pharmaceutically acceptable acid addition salts. The conversion of the non-pharmaceutically acceptable acid addition salts into the pharmaceuticaly acceptable acid addition salts can be carried out, for example, by double decomposition or by liberation of the base and subsequent salt formation with a suitable acid. Those compounds of formula I which possess amphoteric character can, if desired, also be converted into salts with suitable bases. Exemplary of such bases are the'alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or the like.

' The starting materials of formula II are, in part, novel compounds. They can be prepared, for example, by nitrating a compound of the formula 1 1 (VIII) 7 wherein Rand R are as previously described, in the 4- position of the pyrazole' ring with a nitrating acid in a known manner. The resulting 4-nitropyrazole compound of the formula N Cl I 'formamide or a lower alkanol such as methanol or ethanol. A preferred temperature for this reaction is in the range. of from about 50 C. to :about the reflux temperature of the mixture. The pressure at which the reaction is carried out is not critical. The working-up is carriedout by removal of the solvent and crystallization of the residue. The compounds of formula II prepared in this manner can be converted in a known manner to the compounds of formulae III, IV and V.

Compounds of formula 111 can be prepared, for example, by dissolving a compound of formula II in a lower alkanol such as methanol or ethanol and, after the addition of an inert base such as triethylamine, leaving the mixture to stand at room temperature. After completion of the reaction, the solvent is removed and the residue advantageously purified by chromatography;

The compounds of formula III thus obtained can be converted in a simple manner by treatment with ammonia, preferably in a closed vessel, at an elevated temperature, to the amidines of formula IV. A preferred temperature for this treatment is in the range of from about 80 C. to about 120 C. This treatment can also be carried out at a temperature above or below this range, but due to the possibility of decomposition of the reactants, the temperatures utilized should not be too high.

For the preparation of compounds of formula V, a compound of formula II is dissolved in an inert organic solvent, preferably in a mixture of pyridine and triethylamine, and an excess of hydrogen sulfide added to the mixture at room temperature. For the working-up, the reaction-mixture is poured on to water and the reaction product is removed by filtration.

The compounds of formula I are used as medicaments. They are active on the central nervous system. In particular, they possess a psychosedative action of a particular type. For example, it has been found that they have no activity in the anti-pentamethylenetetrazole test but, on the other hand, they exhibit astrong activiy in the mouse fighting test. In addition to this, they have an analgesic and muscle-relaxant activity. On the basis of the foregoing activity profile, the compounds of formula I are particularly suitable for use as tranquilizers in the treatment of psychomatic disorders.

Depending on the substiution, the acute toxicity of the compounds of formula I in mice varies between DL 300 mg./kg. and DL 5000 mg./kg.

The psychosedative or tranquilizing activity of the com- .pounds of formula I can be demonstrated, for example, utilizing the mouse fighting test described hereinafter.

At the beginning of the test, a compound of formula I which is to be tested is administered orally to 20 mice per her of fighting attacks during 3 minutes is registered. When a pair of mice shows 3 or fewer fighting attacks in the observation period of 3 minutes, a protective action of the compound administered, is assumed. Four or more fighting attacks are interpreted as a lack of a protective action.

The dosage which protects half of the pairs of mice, that is, reduces the fighting attacks is denoted as the effective 'dosage 50 percent (ED This is determined by graphical approximation by means of a dosage-activity curve.

The following Table shows the ED values for representative compoundsof formula I.

Table ED50 Compound -mg./kg. p.o. l,3-dimethyl-4-nitropyrazole-S-carboxamidoxime 1.0 O-trimethyl-4-nitropyrazole-S-carboxamidoxime 1.3 O-propyl-1,3-dimethyl-4-nitro-pyrazole-5-carboxamidoxime 6.6 .O-acetyl-l,3-dimethyl-4-nitro-pyrazole-5-carboxamidoxime -r- 3.8 O-isonicotinoyl-1,3-dimethyl-4-nitro-pyrazole 5- carboxamidoxime 8.0 O-ethoxycarbonyl-1,3-dimethyl-4-nitro-pyrazole-5- carboxamidoxime 3.0 O(3-chloropropionyl)-1,3-dimethyl-4-nitro-pyrazole- -5-carboxamidoxime -2 3 8 O-( l-methoxy-l-methylethyl) -1,3-dimethyl-4-nitropyrazole-S-carboxamidoxime 3.8 1-propyl-3-methyl-4-nitro-pyrazole-5-carboxamidoxime 1.8 1-methyl-4-nitro-pyrazole-5-carboxamidoxime 7.2 3-(1,3-dimethyl-4-nitro-pyrazol-i-yl)-4,5-dihydro-5- methyl-1,2,4-oxadiazole 9 3 Q-isobutoxycarbonyl-1,3rdimethyl-4-nitro-pyrazole-S- carboxamidoxime 8.9 O-(Z-bromoethoxy) carbonyl-1,3-dimethyl-4-nitropyrazole-S-carboxamidoxime 9.8

3-( 1,3-dimethyl-4-nitro pyrazol 5-yl) -4,5-dihydro-5,5-

dimethy1-1,2,4-oxadiazole 8 5 4,5-dihydro-5-methyl-3-(3-methyl-4-nitro-l-propylpyrazol-S-yl)-1,2,4-oxadiazole 7.2

, In the treatment of, for example, psychomatic disorders,

the dosage of compounds of formula I will be adapted to the severity of the indications and other special requirements. In a preferred method,'a. compound of formula I isadministered in the form of tablets, which can contain 1 mg, 5 mg. or 10mg. of active ingredient,with repeated administrations indaily doses of 5 mg. to 20 mg., preferably'S mg. to 10 mg. The compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier. Such carrier can be an organic or inorganic inert carrier material which is suitable for enteral or parenteral administration, for example, water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, gums, polyalkyleneglycols, 'or the like. The pharmaceutical preparations can be made upin solid form, for example, as tabletsdragees, suppositories or capsules, or in liquid form, for example, as solutions, suspensions or emulsionsThey may be sterilized and/or may contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They can also contain other therapeutically valuable substances. j

The following Examples further illustrate the process of the invention. EXAMPLE 1 Preparation of '1,3-dimethyl-4-nitropyrazole-5-carbox- H amidoxime v 11.7 g. of hydroxylamine hydrochloride are dissolved in ml. of absolute methanol and treated with a sodium methylate solution .(prepared from 3.6 g. of sodium in 70ml. of absolute methanol) at room temperature. The mixture is stirred for 15 minutesand the precipitated sodium chloride is removed by filtration. The hydroxylamine solution .obtained is added dropwise with stirring Cover aperiod of 4 hours to a. solution of 20 g. of 1,3-

dimethyl-4-nitro-5-cyano-pyrazole in ml. of absolute methanol maintained at 40 C., and the mixture is subsequently maintained for an additional 2 hours at 40 C. After distilling the solvent, the residue obtained is boiled with 200 ml. of absolute tetrahydrofuran. 'I he undissolved portion is separated by removing the solvent by suction and, thereafter, removing the solvent by distillation. After recrystallization from ethanol, 1,3 dimethyl 4 nitropyrazole-S-carboxamidoxime is obtained in the form of yellowish crystals having a melting point of 186-187 C. The hydrochloride crystallized from ethanol/ether forms white crystals having a melting point of 213 C. (decomposition).

In an analogous manner to the foregoing procedure, from 1-propyl-3-methyl-4-nitro-5-cyano-pyrazole there is obtained 3-methyl-4-nitro-l-propylpyrazole 5 carboxamidoxime in the form of yellowish crystals, which after recrystallization from isopropyl ether/ hexane has a melting point of 11O- 11'1 C.

The propyl-3-methyl-4-ni-tro-5-cyano pyrazole starting material can be prepared as follows:

50 g. of 1-propyl 3-methyl 2-pyrazolin 5 one are treated with 100 ml. of phosphorus oxychloride and maintained in a bomb-tube for 12 hours at 130 C. The excess phosphorus oxychloride is removed by distillation in a water-jet vacuum. Thereafter, the residue is taken up in methylene chloride. The organic phase is washed once with a saturated sodium bicarbonate solution, dried over magnesium sulfate and the solvent is removed by distillation. The resulting l-propyl-3-methyl-5 chloro pyrazole boils at 7*2-7 3 C./14 Torr and is immediately reacted further:

76.8 ml. of fuming nitric acid are added dropwise at C. to a solution of 3'8 g. of 1-propyl-3-methyl-5-ch'loropyrazole in 100 ml. of concentrated sulfuric acid in such a manner that the temperature does not rise above 0 C. The mixture is stirred for an additional 4 hours at this temperature and thereafter poured on to 500 g. of ice. The reaction product is taken up in methylene chloride, dried over magnesium sulfate and the solvent is removed by distillation, whereby there are obtained 47.1 g. of 1- propyl-3-methyl-4-nitro-S-chIoro-pyrazole, as a yellow oil which is uniform in the thin-layer chromatogram [Kieselgel plate; e-luant: toluene/ethyl acetate (9: 1): development: UV. light].

'A mixture of 19.75 g. of 1-propyl-3 methyl-4-nitro-5- chloro-pyrazole, 125 ml. of dimethylform-amide, 19.76 g. of potassium cyanide and 0.7 g. of potassium iodide is stirred for 4 hours at 120 C. Thereafter, the solvent is removed by distillation in a water-jet vacuum. The resulting residue is treated with water and extracted with methylene chloride. The organic phase is washed once with a saturated sodium chloride solution, dried over magnesium sulfate and the solvent is removed by distillation. The resulting 1-propyl-3-methyl-4-nitro-S-cyano-pyrazole boils [In an analogous manner to the procedure described in the first paragraph of this Example,.from 1-methyl-4- nitro-S-cyanopyrazole .there is obtained .1-me'thyl-4-nitropyrazole carboxamidoxime as yellow crystals from ethanol having a melting point of 146 C.

The starting material can be prepared as follows:

-24 g. of l-methyl-Z-pyrazolin-S-one are maintained in a bomb-tube for 16 hours at 130-'140 C. with 72 ml. of phosphorus oxychloride. After cooling, the excess phosphorus oxychloride is removed by distillation. The resulting residue is poured on to ice-water and the reaction product extracted with methylene chloride. The solvent dried'over magnesium sulfate and distilled. The resulting 1-methyl-5-chloro-pyrazole boils at 6 5 C./5'1 Torr.

70 ml. of fuming nitric acid are added dropwise at C. to a solution of 25 g. of l-methyl-S-chlorb-pyrazdle in 89.5 ml. of concentrated sulfuric acid and the mixture is then stirred for an additional 4 hours at room temperature. The'reaction mixture is poured on to icewater and extracted with methylene chloride. The organic phase dried over sodium sulfate and the solvent is removed by distillation. The residue obtained crystallizes from ether/ hexane to yield 1-methyl-4-nitro .5 chloro pyrazole as yellow crystals having a melting point of 69 C.

A mixture of 38.3 g. of 1-methyl-4-n'itro 5 -chloropyrazole, 17 g. of potassium cyanide, 1.7 g. of potassium iodide and 300 ml. of dimethylformamide is stirred for 4 hours at 1204130" C. After cooling, the solvent is removed by distillation. The residue is treated with water and extracted with methylene chloride. After drying over sodium sulfate, the solvent is removed by distillation and the residue obtained is treated with ethyl acetate. The precipitated white crystals are recrystallized from ethyl acetate to yield 1-methyl-4-nitro-5-cyano-pyarzole having a melting point of 102 C. is obtained.

In an analogous manner to the procedure described in the first paragraph of this Example, from I-(Z-hydroxyethyl)-3 -methyl-4-nitro cyanopyrazole there is obtained 1-(2-hydroxyethyl)-3-methyl 4 n-i-tropynazole 5 carboxamidoxime as yellowish crystals having a melting point of 15015l C. after recrystallization from isopropyl alcohol.

The 1-(2-hydroxyethyl) 3-methyl-4 nitro 5 cyanopyrazole starting material can be prepared as follows:

'60 g. of 5-methyl-4-nitro-isoxazole are dissolved in 1500 ml. of toluene, treated with 35.6 g. of 2ehydroxyethylhydrazine and the mixture stirred overnight at room temperature. After distillation of the solvent, the mixture is dissolved in warm ethanol. The precipitated l-hydroxyethyl-3-methyl-4-nitro-S-amino-pyrazole is recrystallized from acetonitrile as yellowish crystals having a melting pointof 157-I158 C.

34.0 g. of l-hydroxyethyl 3 methyl-4-nitro-5-aminopyrazole are dissolved in a mixture of 50 ml. of concentrated hydrochloric acid, 250 ml. of glacial acetic acid and 150 ml. of water. Then, there is added dropwise to the solution with stirring at 15 C. a solution of 11.95 g. of sodium nitrite in ml. of water. After completion of the addition, the diazonium salt solution is stirred for an additional 15 minutes. A mixture of 3.6 g. of copper, 10 g. of copper sulfate, 11 g. of sodium chloride, 30 ml. of concentrated hydrochloric acid and 20 ml. of water is maintained for 2 hours at reflux temperature. After cooling, the foregoing diazonium salt solution is added to this solution dropwise with stirring at room temperature, and the resulting mixture is stirred for 1 hour at 60 C. and subsequently overnight at room temperature. The reaction mixture is made alkaline by adding a sodium carbonate solution and is taken up in ethyl acetate. The organic phase is washed with sodium chloride solution, dried over magnesium sulfate and the solvent is distilled. The resulting dark-red oil crystallizes on standing. By recrystallization from ethyl acetate/ petroleum ether there is obtained l-hydroxyethyl 3 methyl-4-nitro-S-chloro-pyrazole as light-beige crystals having a melting point of 81 C.

' 20.0 g. of 1-hydroxyethyl-3-methyl-4-nitro-5-chloropyrazole are dissolved in ml. of dimethylformamide and, after treatment with 7.0 g. of potassium cyanide and 0.7 g. of potassium iodide, the mixture is stirred for 15 hours at 40 C. After the solvent is removed by distillation, the residue is treated with water and taken up in methylene chloride. The organic phase is Washed once with sodium chloride solution, dried over magnesium sulfate and the solvent is distilled. The oil obtained is purified on a 30- fold amount of Kieselgel. The fractions which are eluted with a toluene/ethyl acetate (8:2) solvent mixture and which are uniform in the thin-layer chromatogram are collected. The resulting 1-hydroxyethyl-3-methyl-4-nitr0- S-cyano-pyrazole is obtained as beige crystals having a melting point of 73 74 C. after recrystallization from isopropyl ether.

In an analogous manner to the procedure described in the first paragraph of this Example, from 1-vinyl-3-methyl-4-nitro-S-cyano-pyrazole there is obtained 1-vinyl-3- 1 1 methyl-4-nitro-pyrazole-5-carboxamidoxime as yellowish crystals having a melting point of 185 186" C.'

p The 1-vinyl-3-methyl-4-nitro-5-cyano-pyrazole starting material can be prepared as follows:

75 g. of 1-hydroxyethyl-3-methyl-S-hydroxy-pyrazole are treated with 300 ml. of phosphorus oxychloride and the mixture is maintained for 15 minutes at reflux temperature. After distilling the excess phosphorus oxyehloride, the residue is treated with ice and shaken out with methylene chloride. The organic phase is washed successively with water, saturated sodium bicarbonate solution and water, dried over magnesium sulfate and the solvent is distilled. The resulting red-brown oil is distilled toyield 1-chloroethyl-3-methyl-5-chloropyrazole as a colorless liquid having a-boiling point of 72-75 C./8 Torr; nn =1.5092. I

57.1 g. of 1-chlor'oethyl-3-methyl-5-chloro-pyrazole are added dropwise with stirring at 10 C. to 132ml. of concentrated sulfuric acid. Thereafter, the mixture is cooled to -5 C. and 153 ml. of fuming nitric acid are added dropwise at this temperature. The mixture is maintained at this temperature for 4 hours and stirred overnight at room temperature. It is then poured on to 1 kg. of ice and extracted twice with 1 liter of methylene chloride eachtime. The organic phase is washed with water, dried over magnesium sulfate and the solvent is distilled. The crystalline residue obtained is recrystallized from ethyl acetate/petroleum ether to yield 1-chloroethyl-3-methyl- 4-nitro-5-chloro-pyrazole as beige crystals having a melting point of 68 69 C.

60 g. of 1-chloroethyl-3-methyl-4-nitro-S-chloro-pyrazole are dissilved in 300 ml. of dimethylformamide and, after treatment with 17.4 g. of potassium cyanide and 1.8 g. of potassium iodide, the mixture is maintained for 4 hours at 120 C. Subsequently, the solvent is removed by distillation. After treatment with water, the mixture is taken up in methylene chloride. The organic phase is washed with water, dried over magnesium sulfate and the solvent is distilled. The residue obtained is chromatographed on a 30-fold amount of Kieselgel. The fractions eluted with toluene which are uniform on the thin-layer chromatogram are collected and the solvent is distilled. The resulting oil crystallizes on sprinkling with isopropyl ether to yield l-vinyl-3-methyl-4-nitro-5-cyano-pyrazole as yellowishlcrystals having a melting point of 61 62" C. from isopropyl ether.

EXAMPLE 2 Preparation of 1,3-dimethyl-4-nitropyrazole-5- carboxamidoxime A solution of 9.9 g. of 1,3-dimethyl-4-nitropyrazole-5- carboxamidic acid methyl ester in 100 ml. of absolute methanol is stirred for 4 hours at an internal temperature of 40 C. with a solution of 1.7 g. of hydroxylamine in 70 ml. of absolute methanol. After removing the solvent by distillation, the residue obtained is recrystallized from ethanol to yield 1,3-dimethyl-4-nitropyrazole-5-carboxamidoxime having a melting point of 186-187 C.

The starting material can be prepared as follows:

20.0 g. of 1,3-dimethyl-4-nitro-S-cyano-pyrazole are dissolved in 100 ml. of absolute methanol and after treatment with 2 ml. of triethylamine, the mixture is allowed to stand for 4 days at room temperature. After removing the solvent by distillation, the residue is chromatographed on a 30-fold amount of Kieselgel. The ethyl acetate eluates which are uniform in the thin-layer chromatogram (Kieselgel' plate; eluant: methylene chloride/2 percent methanol; development: U.V. light) are collected. The white crystals of 1,3-dimethyl-4-nitro-pyrazole-S-carboximidic acid methyl ester obtained after the solvent is removed by distillation have a melting point of 9293 C. after recrystallization from ethyl acetate/petroleum ether (low boiling).

EXAMPLE 3 Preparation of 1,3-dimethyl-4-nitropyrazole-5- carboxamidoxime 0.904 g. of hydroxylamine hydrochloride are dissolved in 20 ml. of absolute methanol. The solution is treated with 0.648 g. of sodium methylate, stirred for 15 minutes, the precipitated sodium chloride is removed by filtration. The filtrate is added dropwise to a solution of 1.83 g. of 1,3-dimethyl-4-nitropyrazole-S-carboxamidine at 40 C. and the mixture subsequently maintained for 20 hours at reflux temperature. After the methanol is removed by distillation, the residue obtained is chromatographed on a 30-fold amount of Kieselgel. The ethyl acetate eluates which are uniform in the thin-layer chromatogram (Kieselgel; eluant: ether; development: U.V. light), are collected and the solvent is removed by distillation. After recrystallization from alcohol, there are obtained yellowish crystals of 1,3-dimethyl-4-nitropyrazole-S-carboxamidoxime having a melting point of 186-187 C.

The starting material can be prepared as follows:

- 2.5 g. of 1,3-dimethyl-4-nitropyrazole-5-carboximidic methyl ester are treated with 20 ml.-of saturated solution of ammonia in methanol and maintained in a'bomb-tube overnight at C. After removing the solvent by distillation, the residue is dissolved in hot'ethyl acetate, treated with activated charcoal and, after concentration to a small volume, left to stand. The crystals obtained are recrystallized from ethyl acetate to yield 1,3-dimethyl- 4-nitropyrazole-S-carboxamidine as light yellow crystals having a melting point of 148150 C.

EXAMPLE 4 Preparation of 1,3,0-trirnethyl-4-nitropyrazole-5- carboxamidoxime A solution of 3.3 g. of 1,3-dimethyl-4-nitropyrazoyle- 5-carboxamidoxime in 150 ml. of absolute alcohol is treated with a sodium ethylate solution (prepared from 0.383 g. of sodium in 20 ml. of absolute ethanol). The mixture is stirred for 5 minutes at room temperature, and a solution of 2.83 g. of methyl iodide in 20 ml. of ethanol is added dropwise thereto at 15 C. The resulting mixture is subsequently maintained for 2 hours at reflux temperature. After removing the solvent by distillation, the product obtained is rapidly purified on a 10-fold amount of Kieselgel. The 1,3,0-trimethyl-4-nitropyrazole- S-carboxamidoxime formed is eluted with chloroform. From ethyl acetate/hexane, there is obtained 1,3,0-trimethyl-4-nitropyrazole 5 carboxamidoxime as yellow crystals having a melting point of 116 C.

In an analogous manner there can be prepared:

O-Ethyl 1,3 dimethyl-4-nitropyrazole-5-carboxamidoxime as lemon-yellow crystals from cyclohexane, having a melting point of 9394 C.'

O-Propyl 1,3 dimethyl-4-nitropyrazole-S-carboxamidoxime as a yellow oil. Mass spectrum: peaks (m/e) at 241, 224, 222, 182, 181, 151, 136.

EXAMPLE 5 Preparation of O-(l-methoxy-1-methylethyl)-1,3- dimethyl-4-nitropyrazole-5-carboxamidoxime A mixture of 5 g. of 1,3-dimethyl-4-nitro-pyrazole-5- carboxamidoxime and 100 ml. of acetone dimethyl acetal is maintained for 36 hours at reflux temperature. After distilling off the excess solvent, the residue obtained is chromatogrephed on 350 g. of Kieselgel. The chromatographically uniform methylene chloride/ 5 percent methanol eluates are collected, the solvent distilled off and the crystalline residue obtained recrystallized. from 'ether/ hexane. There are obtained white crystals of .O-(l-methoxy 1 methylethyl)-l,3-dimethyl-4-nitropyrazole-5- carboxamidoxime of melting point of 131 C.

13 XA L 6.

Preparation of OracetyI-1,3:dimetliyl-4-nitropyrazole- 3; carboxamidoxime v A- solution of 4.0 g. of acetyl chloride in 2.0 ml. of ether is added dropwise with stirring at room temperature to a solution of 9.9 g. of 1,3-dirnethyl-4-nitropyrazole-5- carboxamidoxime in 80 ml. of pyridinel -The mixture is subsequently stirred for an additional 2 hours. After the solvent is removed by distillation in a'water-iet vacuum, the yellow oil obtained is treated with water and shaken outwith ethyl acetate. The organic phase is washed with ice-cold sodium carbonate solution and subsequently with saturated sodiumchloride solution, dried over magnesium sulfate and the solvent is distilled. The crystalline residue obtained is recrystallized from ethyl acetate/hexane, to yield ..OQacetyI-1,3Pdimethyl-4-nitropyrazole-5-carboxamidoxime as white crystals having a melting point of 174 C.

In an analogous manner there can .be, prepared:

O-Propionyl 1,3 dimethyl-Amitropyrazole-S-carboxamidoxirne, white crystals from ethyl acetate/hexane, having a melting point of l83"184 C;

0 Butyryl-v 1,3 dimethylA-nitropyrazole-S-carboxamidoxime, white crystals from point of l55-'l57 C. I

0 Benzoyl-1,3-dimethyl-4-nitropyrazole-5 carboxamidoxime, white crystals from ethanol having a melting point of 166-168 C. I

'O-Nicotinoyl 1,3 dimethyl-4-nitropyrazole-S-carboxamidoxime, white crystals from ethanol,- having a melting point of 2.06''108-C.' v a Y I O-Cinnamoyl 1,3 dimethyl-4-nitropyrazole-S-carboxamidoxime, white crystals from'ethanol, having a melting point of 171-173 C.

O-Phenylacetyl 1,3 dimethyl 4 nitropyrazole-S- carboxamidoxime, white crystals from ethanol, having a melting point of 13-8--139 C. 1

O-Hydrocinnamoyl 1,3 dimethyl-4-nitropyrazole-5- carboxamidoxime, white crystals from ethanol, having a melting-point of '148-149 C. r

Y O-Cyclohexylcarbonyl 1,3 dimethyl-4q'1itropyrazolecarboxamidoxime, white crystals from isopropyl ether, having a melting point of 173 --174 C.

-O-(3-chloropropionyl) 1,3 dimet yl-fi-nitropyrazole- S-carboxamidoxirne, white crystals from ethanol/hexane, having a melting point of v1105-112" C. i, a O-Isonicoti oyl 1,3 diniethyl-nitropyrazole-S-can hoxamidoxime, white crystals from ethanol, having a melting point of 1-73 -174. C. 1

, O-(p-Chlorobenzoyl). 1,3,.- dimethyllrnitropyrazole- S-carboxamidoxime, white crystals from ethanol, having a melting point of-181-l-82. C. I i 1 O-(3,4,5 Trimethoxybenzoyl); 1,3- dimethyl-4-nitropyrazole-S-carboxamidoxime, white crystals fromethanol,

having a melting point of 198200 C.

Starting from 1-methyl-4-nitropyrazole-S-carboxarni- Preparation ethanol, having a melting tetrahydrofuran and 4.4 ml. of pyridine and the mixture is L nitropyrazole-S-carboxamidoxime as white crystals having a melting point of 212 C.

In an analogous manner there can be prepared:

O-Butoxycarbonyl 1,3 dimethyl-4-nitropyrazole-5- carboxamidoxime, white crystals from tetrahydrofuran/ hexane, having a melting point of l33l34 C.

. O-Isopropoxycarbonyl 1,3 dimethyl-4-nitropyrazole- 5,-carboxamidoxime, white crystals from tetrahydrofuran, having a melting point of 199 201 C.

O-Isobutoxycarbonyl 1,3 dimethyl-4-nitropyrazole S-carboxamidoxime, white crystals from tetrahydrofuran, having a melting point of 139-141 C.

O-(Z-Bromoethoxy)carbonyl 1,3 dimethyl-4-nitropyrazole-S-carboxamidoxirne, white crystals from tetrahydrofuran/hexane, having a melting point of 164- 165 C.

O-Allyloxycarbonyl 1,3 dimethyl-4-nitropyrazole-S- carboxamidoxime, white crystals from tetrahydrofuran, having a melting point of 158-160 C.

p In an analogous manner, starting from 1-methyl-4- nitro-pyrazole-S-carboxamidoxime there is obtained 0- ethoxycarbonyl 1 methyl-4-nitropyrazole 5 carboxamidoxime, white crystals from tetrahydrofuran, having a melting point of 154-155 C.

EXAMPLE 8 Preparation of 3-(1,3-dimethyl-4-nitropyrazo1-S-yl)-4,5- dihydro-S-methyl-1,2,4-oxadiaz0le 44 g. of acetaldehyde are added dropwise with stirring to a suspension of 19.9 g. of 1,3-dirnethyl-4-nitropyrazole- S-carboxyarnidoxime in 1000 ml. of ethanol maintained at 5 C., the temperature rising to 20 C. and amidoxime passing into solution. After the mixture has been stirred for an additional 1 hour at room temperature, the mixture is maintained overnight at reflux. Thereafter, the solvent is removed by distillation and the residue obtained chromatographed on 350 g. of Kieselgel. The uniform methylene chloride/5 percent methanol eluates are collected. The solvent was removed by distillation and the crystals obtained recrystallized from ethyl acetate/hexane to yield 3-(1,3-dimethyl-4-nitropyrazol-S-yl)-4,5-dihydro- 5-methyl-1,2,4-oxadiazole as yellow crystals having a melting point of C.

In an analogous manner there can be prepared:

3-(1,3 dimethyl 4 nitropyrazol-S-yl)-4,5-dihydro-5- propyl-1,2,4-oxadiazole, yellowcrystals having a melting point of 86 C.

, 4,5-dihydro 5 methyl-3-(3-methyl-4-nitro-1-propylpYrazol-S-yl)-1,2,4-oxadiazole, yellow crytals from hexane, having a melting point of 67 68 C.

' 3-(3-methyl 4 nitropyrazol-S-yl)-4,5-dihydro-5-methyl-1,2,4-oxadiazole, yellow crystals from methylene chloride/ hexane, having a melting point of 84 C.

EXAMPLE 9 EXAMPLE 10 Preparation of 3-(1,3-dimethyl-4-nitropyrazol-S-yl)-I- 'oxa-ZA-diazospiro[4,5]dec-2-ene Q Ajmix-ture-of 16.0 g. of 1,3-dimethyl-4-nitropyrazole-5- carboxamidoximeand 50 ml. of cyclohexanone is stirred for '12 hours in an oil-bath at a temperature of 100 C.

EXAMPLE 11 Preparation of 3-( l,3-dimethyl-4-nitropyrazol -yllf P 4,5-dihydro-5,S-dimethyl-1,2,4-oxadiazol 5.0 g. of 1,3-dimethyl-4-nitropyrazole-5-carboxamid oxime are treated with 50 ml. of acetone and the mixture is maintained for 24 hours in a bomb-tube a't 100C. After the excess solvent is removed by wdistilla.tior 1 ,.the residue obtained is treated with 70 ml. of methylene chloride. The mixture is boiled for a short time and freed from the insoluble portion by filtration. After, distilling the solvent, the residue obtained is chromatographed 'ona 30-fold amount of Kieselgel. The fractions which are eluted with methylene chloride/5 percent methanol and which are uniform in the thin-layer chromatogram, are combined, the solvent distilled olf and the residue obtained recrystallized from ethyl acetate/hexane. There are obtained yellow crystals of 3-(l,3-dimethyl=4-nitropyrazol- 5-yl)-4,5-dihydro-5,5-dimethyl-1,2,4-oxadiazole of melting point l31132 C.

EXAMPLE 12 Preparation of O-methoxymethyl-l,3-dimethy1- 4-nitropyrazole-5-carboxamidoxime 5 g. of 1,3-dimethyl-4-nitropyrazole-5-carboxamidoxime are dissolved in 50 ml. of absolute dimethylformamide, the mixture is cooled to 40 C. and 2.03 g. of sodium methylate are added at this temperature. After stirring for minutes at this temperature, 3.0 ml. of chlorodimethyl ether added dropwise. After 0.5 hour, the mixture is poured onto ice-water and shaken outwith chloroform. The organic phase is washed once with water, dried over magnesium sulfate and the solvent is distilled. The oil obtained is chromatographed on a -fold amount of Kieselgel (granule size 0.05-0.02 mm.) using toluene/ ethyl acetate (9:1) as the eluting agent. The fractions obtained are combined and evaporated. The residualoil is crystallized from n-hexane and thereafter recrystallized from ethyl acetate/ petroleum ether (4045 C.) to yield O-methoxymethyl-l,3-dimethyl-4-nitropyrazole 5 carboxamidoxime as light-yellow crystals having a melting point of 107-108 C.

The following Examples illustrate typical pharmaceutical preparations containing the pyrazole derivatives of the invention.

EXAMPLE 13 Preparation of capsules A compound of Formula I (hereinafter referred'to as active ingredient) can be incorporated in capsules having the following composition:

Active ingredient Lactose Corn starch Talc EXAMPLE '14 Prep' rfion of tablets 7 A compound offormula I (hereinafter referred to as active.ingred ient.) can be incorporated in tablets having .the followingcomposition:

- The activein'gre'dient and the remaining ingredients-are mixed well. The-mixture is compressed:onabtabletting machine-to slugs of about 2.5 cm. diameter and 0.8 cm: thickness which -are then "comminuted to a *granulate (about 1.2 mm:).- The granulate so obtained iscompressed to mg. tablets. z z AMP 1 f." Preparationof drages The compounds o f'formula I' (hereinafter referred to as"active" ingredient) can be incorporated in 'drages having the following composition: a v Core: h H I ,Mg-

Active ingredient 2 I Mannitol;v 1 -88 Talc 5 Corn starch 15 Core weight. -s- 1 10 Coating mass;-

- 1, Sug BQ pe en Rice starch 5 percent Y Y. 1-50 l se t- -sa... weight Y v v@110 Drage weight-n;

' The active ingredient" is mixed'with the mannitol and passed" through am. 5 sieve (mesh width about 0.23 mm.). The corn starch is boiled with'water to'give" a 10 percent pasteZ'The powdery mixture is homogeneously triturated with the corn starch fiastejThe slightly moist mass is granulated by means of a No. 3 sieve (mesh 'width' about 1.0 mm."). 'The materialfor compression is compressed to biconvexcoresof 150 mg. weight.'The cores have a diameter of approximately 8.0 mm. I

The resulting cores are coated with sugar according to the usual coating process utilizing sugar syrup up to final weight of 300 mg. a 1.

"We claimr "'1. A compound of the formulae: 1

TN L

olf \NLTI If v p "it 7y athei m Rislowen 51km. halo-lower allryl, hydroxyilower alkyl, lowe r. alkoxy lower ,alkyl or lower akenyl; R is hydrogen, or lower alkyl and .R is-a radical of thelformula wherein R is hydroxy, lower alkoxy, halo-lower alkoxy or lower alkoxy-lower alkoxy or a pharmaceutically ac ceptable acid addition salt thereof.

2. A compound in accordance with claim 1, wherein R is lower alkyl.

3. A compound in accordance with claim 2, wherein R is hydrogen.

4. A compound in accordance with claim 2, wherein R is lower alkyl.

5. A compound in accordance with claim 1, wherein R is (lower alkoxy)-(lower alkoxy).

6. A compound in accordance with claim 1, 1,3-dimethyl-4-nitropyrazole-5-carboxamidoxine.

7. A compound in accordance with claim 1, 3-methy1- 4-nitro-1-propylpyrazole-S-carboxamidoxime.

8. A compound in accordance with claim 1, l-met-hyl- 4-nitropyrazole-5-carboxamidoxime.

9. A compound in accordance with claim 1, 1,3,0-trimethyl-4-nitropyrazole-S-carboxamidoxime.

10. A compound in accordance with claim 1, O-ethyl- 1,3-dimethyl-4-nitropyrazole-S-carboxamidoxime.

11. A compound in accordance with claim 1, O-propyl- 1,3-dimethyl4-nitropyrazole-5-carboxamidoxime.

12. A compound in accordance with claim 1, O-(lmethoxy-l-methylethyl) 1,3 dimethy1-4-nitropyrazole- S-carboxamidoxime.

13. A compound in accordance with claim l, O-methoxymethyl-1,3-dimethyl 4 nitropyrazole-S-carboxamidoxime.

14. A compound in accordance with claim 1, O-3-meethoxypropyl 1,3 dimethyl-4-nitropyrazole-5-carbox amidoxime.

15. A compound in accordance with claim 1, 1-(2-hydroxyethyl) 3 methyl-4-nitropyrazo1e-S-carboxamidoxime.

16. A compound in accordance with claim 1, l-vinyl- 3-methyl-4-nitropyrazole-5-carboxamidoxime.

References Cited Long et al.: J. Heterocycl. Chem., 1970, vol. 7, pp. 863-9.

NATALIE TROUSOF, Primary Examiner US. Cl. X.R.

260240 A, 295 R, 295.5 R, 307 G, 310 A; 424263, 266, 272, 273

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,822,283 Dated July 2, 1974 Inventm-(s) Hans Bruderer Rolf Richle and Rudolf Ruegg It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 6, after "Ser. No. 296,691" insert Claims priority, applications Switzerland, October 22, 1971, No. 15404/71 and September 12, 1972, No. 13327/72.

formula Column 16, claim 1, lines 57-62, delete the formula N -R 3 -C Column 16, Claim 1, line 69, "akenyl" should be:

alkenzl Signed and sealed this 18th day of March 1975.

(SEAL) Attest:

C. MARSHALL DANN Commissioner of Patents and Trademarks RUTH C. MASON Attesting Officer 

